Remaining Hopeful In Alzheimer’s Research

Too many times in the last decade, millions of people with Alzheimer’s disease and their families have had their hopes dashed by failures of clinical trials that had raised expectations for discovering a “miracle” treatment to cure, slow, or prevent this devastating illness.

The latest setback came earlier this year with the announcement by another major pharmaceutical firm that it had discontinued its study of an investigational drug being tested on 1,400 patients who showed mild cognitive impairment in the early stage of this progressive brain disease that affects some 5 million Americans.

As a clinician and researcher, I have spent more than 30 years working on Alzheimer’s, and I want to urge everyone who cares deeply about the outcome to summon the patience and maintain the faith that someday we will find a way to prevent this heartbreaking illness.

We must remember that this race for a treatment is a grueling marathon. It was never going to be a simple sprint. And clinical trials currently underway — including those that I am helping to direct as part of the Banner Alzheimer’s Institute’sAlzheimer’s Prevention Initiative — may yet someday carry us across the finish line.

The majority of recent clinical trials have been built around the “amyloid hypothesis,” which posits that an unusual buildup of the amyloid protein, commonly seen in Alzheimer’s patients, causes the neurodegenerative effects by creating waxy plaques that essentially strangle brain tissue.

Two recent unsuccessful clinical trials have focused on trying to find a way to block an enzyme called BACE that plays a role in producing toxic amyloid. Both studies used a particular BACE inhibitor, but neither succeeded. Significantly, a common element of these unsuccessful experiments is that all the Alzheimer’s patients on whom the drugs were tested were already showing varying degrees of symptoms of the disease and/or elevated brain amyloid. We can infer from these facts that the patients already had fairly extensive brain damage. In addition, the studies enrolled people who, on average, were old enough to be at risk for other age-related brain problems that might not be responsive to this therapy.

Our clinical trials, however, which we call the Generation Program, are groundbreaking because the most promising therapies are being tested on more than 3,000 volunteers between the ages of 60 and 75, who are all cognitively healthy and at reduced risk of having other age-related brain problems unrelated to Alzheimer’s. Moreover, our participants were painstakingly selected because they are at particularly high risk of developing symptoms of Alzheimer’s, based on their genetic makeup. They all carry one or two copies of the gene known as APOE4, which has been linked to an increased likelihood of the disease.

We and our trial partners, Novartis and Amgen, believe that the distinctive features of our studies — large cohorts of people without symptoms but at high risk who will be studied for a long treatment duration of 5-8 years — as well as the use of a late-stage BACE inhibitor, give us a better chance of preventing, slowing, or stopping the disease, before the brain is ravaged.

The vast majority of experiments fail. That is the nature of scientific inquiry. I’m reminded of the saying, “99 percent of success is based on failure.” Indeed, this is how science advances — you generate a hypothesis, you test it, you get the answers, and you revise your thinking and move on. If you do it correctly, you learn crucial information either way — whether the drug is successful or even if it’s not.

We live in an age when people expect quick results, and the expectation is often heightened by media coverage that raises the hopes of families desperate for good news. But failure can be very constructive. The devil is always in the details, so it is crucial to remember that seemingly small variations in the molecular substances being tested and in the design of the studies can yield hugely different results.

We remain in this race for the long haul, and we urge researchers, corporations, funders, and the public to hang in there with us.

Pierre N. Tariot, M.D. is the director of the Banner Alzheimer’s Institute and co-principal investigator of the Alzheimer’s Prevention Initiative Generation Study. He has been involved in more than 100 research studies and has participated in publishing more than 350 papers in the field.